Antiviral Response Dictated by Choreographed Cascade of Transcription Factors

Abstract

The dendritic cell (DC) is a master regulator of immune responses. Pathogenic viruses subvert normal immune function in DCs through the expression of immune antagonists. Understanding how these antagonists interact with the host immune system requires knowledge of the underlying genetic regulatory network that operates during an uninhibited antiviral response. To isolate and identify this network, we studied DCs infected with Newcastle disease virus, which is able to stimulate innate immunity and DC maturation through activation of RIG-I signaling, but lacks the ability to evade the human IFN response. To analyze this experimental model, we developed a new approach integrating genome-wide expression kinetics and time-dependent promoter analysis. We found that the genetic program underlying the antiviral cell-state transition during the first 18 h postinfection could be explained by a single convergent regulatory network. Gene expression changes were driven by a stepwise multifactor cascading control mechanism, where the specific transcription factors controlling expression changed over time. Within this network, most individual genes were regulated by multiple factors, indicating robustness against virus-encoded immune evasion genes. In addition to effectively recapitulating current biological knowledge, we predicted, and validated experimentally, antiviral roles for several novel transcription factors. More generally, our results show how a genetic program can be temporally controlled through a single regulatory network to achieve the large-scale genetic reprogramming characteristic of cell-state transitions.